Abstract
Platinum-based therapeutics are used to manage many forms of cancer, but frequently result in peripheral neuropathy. Currently, the only option available to attenuate chemotherapy-induced neuropathy is to limit or discontinue this treatment. Sphingosine 1-phosphate (S1P) is a lipid-based signaling molecule involved in neuroinflammatory processes by interacting with its five cognate receptors: S1P1-5 In this study, using a combination of drug pharmacodynamic analysis in human study participants, disease modeling in rodents, and cell-based assays, we examined whether S1P signaling may represent a potential target in the treatment of chemotherapy-induced neuropathy. To this end, we first investigated the effects of platinum-based drugs on plasma S1P levels in human cancer patients. Our analysis revealed that oxaliplatin treatment specifically increases one S1P species, d16:1 S1P, in these patients. Although d16:1 S1P is an S1P2 agonist, it has lower potency than the most abundant S1P species (d18:1 S1P). Therefore, as d16:1 S1P concentration increases, it is likely to disproportionately activate proinflammatory S1P1 signaling, shifting the balance away from S1P2 We further show that a selective S1P2 agonist, CYM-5478, reduces allodynia in a rat model of cisplatin-induced neuropathy and attenuates the associated inflammatory processes in the dorsal root ganglia, likely by activating stress-response proteins, including ATF3 and HO-1. Cumulatively, the findings of our study suggest that the development of a specific S1P2 agonist may represent a promising therapeutic approach for the management of chemotherapy-induced neuropathy.
Highlights
Platinum-based therapeutics are used to manage many forms of cancer, but frequently result in peripheral neuropathy
There was no change in total Sphingosine 1-phosphate (S1P) concentration (Fig. 1B), when the five most abundant S1P species were considered individually, plasma levels of d16:1 S1P were significantly increased after oxaliplatin treatment (Fig. 1C)
This suggests that an increase in d16:1 content would favor pro-inflammatory S1P1 signaling [31] at the expense of S1P2, suggesting that attenuation of S1P2 signaling may contribute to peripheral neuropathy
Summary
LC-MS/MS was used to quantify S1P (Fig. 1A) in the plasma of cancer patients prior to and after an oxaliplatin treatment. Co-administration of CYM-5478 resulted in a delay in the loss of body mass, becoming statistically significant 2 days later than the cisplatin-only group This suggests that CYM-5478 itself does not result in general toxicity and may attenuate the adverse effects of cisplatin. There were no apparent morphological abnormalities of the DRGs (data not shown), axons in the dorsal root of cisplatin-treated rats were characterized by irregularities in their myelin sheaths. These irregularities were absent in cisplatin-treated rats that received CYM-5478 (Fig. 4, A–C). Higher magnification revealed axons with widespread loss of myelin sheath integrity and disintegration of the axoplasm These characteristics were largely absent from the axons of rats treated with both cisplatin and CYM-5478
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